**4. PASK hypothalamic function in food intake and energy homeostasis**

The hypothalamus is the key to controlling food intake. The identification of hypothalamic glucose sensing systems and neuronal populations expressing and responding to orexigenic and anorexigenic peptides (see Section 2.1) has focused the studies on the hypothalamic nuclei. They have been specifically directed toward identifying the mechanisms involved in controlling nutrient sensing, feeding behavior and its relationship with insulin actions in the central nervous system in order to regulate energy and glucose homeostasis. Hypothalamic metabolic sensors

respond in opposite ways to changes in nutrients and orexigenic or anorexigenic peptides, and their activation/inhibition regulates food intake. For example, the hypothalamic AMPK is activated by fasting and inhibited by refeeding [53, 57, 102], and the mTORC1/S6K pathway is activated by glucose and amino acids, inhibiting food intake [20, 57, 103]. Both pathways are involved in controlling feeding and regulating the energy balance.

In 2013, PASK was identified in the hypothalamic areas involved in feeding behavior, and its expression was regulated under fasting/refeeding conditions [104, 105]. It was proposed as a hypothalamic and liver nutrient sensor and a general regulator of glucose metabolism and cellular energy. Moreover, PASK−/− mice resist diet-induced obesity [93]; it might therefore be understood that PASK could control the hypothalamic function related to intake control. For example, elevated glucose levels decrease mRNA coding to PASK in VMH and LH areas in hypothalamic organotypic cultures and in neuroblastoma N2A cells [104]. The PASK expression is also regulated *in vivo* in response to fasting/refeeding conditions. This effect is clearer in LH: mRNA coding to PASK is lower under fasting conditions and increases in response to refeeding conditions [105]. The effect observed after refeeding *in vivo* is the opposite to the glucose effect found in VMH and LH in hypothalamic organotypic cultures and neuroblastoma N2A cells. However, the effect is similar to those produced in the presence of both glucose and the anorexigenic peptide GLP-1 (an incretin release from intestinal L-cells in response to feeding) [106, 107]. The role of PASK in the hypothalamus would be similar to other well-known metabolic sensors, such as AMPK and mTORC1. The activation of AMPK and mTORC1 is coordinated and antagonistic. While AMPK is activated by a fall in energy, mTORC1 is activated by its increase. Hypothalamic metabolic sensors, such as AMPK and mTORC1, therefore play an important role in feeding behavior, body weight homeostasis, and energy balance (see Section 2.1). These sensors respond to changes in nutrient levels in the VMH and LH (hypothalamic areas involved in feeding behavior) and in neuroblastoma N2A cells, and those effects are modulated by the GLP-1 in lean and obese rats [57].

Studies in PASK−/− mice have indicated that PASK-deficiency involves a downregulation of mRNA levels coding to AMPKα2 in VMH, and slightly so in LH [105], while impairing the coordination of the AMPK and mTORC1/S6K1 pathways. Thus, both the AMPK and mTORC1/S6K1 pathways are surprisingly activated at the same time under fasting and feeding conditions in PASK−/− mice [105]. This finding could mean that the inhibition of mTORC1/S6K through AMPK activation requires the coordinated phosphorylation of TSC2 by Glycogen synthase kinase 3β (GSK3β) [59], which is a PASK substrate *in vitro,* and PASK deficiency could therefore alter hypothalamic GSK3β activity [108]. Additionally, this study has found that the exendin-4 regulatory effect on metabolic sensor activity is lost in PASK−/− mice, and the anorexigenic properties of exendin-4 significantly reduced, suggesting that PASK could be a mediator in the brain GLP-1 signaling pathway. Some of the antidiabetogenic effects of exendin-4 might be modulated through these processes. This means that hypothalamic PASK, interacting with AMPK and mTORC1 pathways, and in coordination with anorexigenic/orexigenic peptides, could be a key enzyme in food intake control, and in peripheral tissue functions, such as brown adipose tissue thermogenesis, pancreatic insulin secretion, etc. However, more studies are needed to clarify this hypothesis and the putative molecular mechanism of PASK actions in whole-body physiology.

The downregulation of mRNA coding to AMPKα2 and the modulation of the GLP-1 effects in hypothalamus in PASK−/− mice suggest that both effects may also be regulating thermogenesis in BAT and the browning of white fat, as both processes are mediated by the inhibition of hypothalamic AMPK [109, 110].

**353**

in the cytoplasm [116, 119].

*Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes*

**5. PASK contribution to hepatic adaptation to fasting/feeding**

ological ranges, and therefore for the proper control of diabetes.

As well as acting in hypothalamic functions, PASK also has key functions in the peripheral tissues. For example, diabetes and PASK have been linked, as a human mutation of the *PASK* gene has been correlated with maturity-onset diabetes of the young (MODY). This mutation increases kinase activity and decreases glucosestimulated insulin secretion by the pancreas [111]. In addition, decreased PASK expression in pancreatic islets has been reported in human T2D [88]. The PASK function in peripheral tissues could be crucial for maintaining metabolic and

The liver maintains metabolic homeostasis, and it is especially essential in the proper control of glucose during fasting and feeding periods. In particular, the liver is one of the main insulin-responsive organs, so it records a greater glucose uptake when glycaemia rises, storing it as glycogen (see Section 2.1). By contrast, when blood glucose falls, and other organs require energy, the liver produces glucose by glycogenolysis and gluconeogenesis. Therefore, the correct hepatic response to insulin and hepatic metabolism are critical for maintaining glycaemia within physi-

Studies with PASK−/− mice have reported the critical role PASK plays in hepatic

A good example of PASK deficiency effects under feeding involves the changes recorded in GCK, which is a critical enzyme in the hepatic function. GCK is an enzyme involved in hepatic glucose sensing (see Section 2). This enzyme is activated by the increase in blood glucose which occurs in feeding periods. It therefore adjusts hepatic glucose phosphorylation to blood glucose levels, acting as a glucose sensor. The importance of GCK in maintaining glucose homeostasis is evidenced by the severe impacts caused by mutations in the GCK gene. The loss of GCK function in the human body causes maturity-onset diabetes of the young type 2 (MODY2) [114]. By contrast, activating mutations generate persistent hyperinsulinemia [115]. Many liver functions are controlled by GCK, which acts together with insulin in the maintenance of blood glucose homeostasis [116], and the activation of glycolytic and lipogenic gene expression. GCK is also involved in glycogen synthesis and storage in the liver [117]. The enzymatic activity of GCK is controlled by transcriptional and posttranscriptional mechanisms. While the transcriptional regulation of the GCK gene is basically insulin-dependent [118], the posttranscriptional mechanisms of regulation involve interaction with other proteins, highlighting the glucokinase regulatory protein (GCKR). GCKR modulates GCK activity when glucose levels decline by binding and sequestering it in the nucleus, and thus avoiding its function

adaptation to fasting/feeding periods, especially under an HFD [93, 112]. It is interesting that PASK expression is regulated in the liver by fasting/feeding, with fasting downregulating it [112]. Moreover, Perez-Garcia et al. [113] have found that PASK deficiency alters the complex hepatic response to fasting/feeding. The expression of the transcription factors and key enzymes that regulate gluconeogenesis and mitochondrial fatty acid transport under fasting conditions is altered in PASK−/− mice, with lower forkhead box protein O1 (*Foxo 1*) and carnitine palmitoyltransferase 1A (*Cpt1a*) and higher peroxisome proliferator-activated receptor alpha (*Ppara*). Similarly, PASK deficiency modifies the activity of the protein kinase B (AKT) overactivated under fasting and the stability of phosphoenolpyruvate carboxykinase (PEPCK) [113], while no detectable changes have been observed in the maintenance of blood glucose homeostasis during prolonged

*DOI: http://dx.doi.org/10.5772/intechopen.95454*

energy homeostasis.

fasting periods [105].

#### *Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes DOI: http://dx.doi.org/10.5772/intechopen.95454*

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

regulating the energy balance.

respond in opposite ways to changes in nutrients and orexigenic or anorexigenic peptides, and their activation/inhibition regulates food intake. For example, the hypothalamic AMPK is activated by fasting and inhibited by refeeding [53, 57, 102], and the mTORC1/S6K pathway is activated by glucose and amino acids, inhibiting food intake [20, 57, 103]. Both pathways are involved in controlling feeding and

In 2013, PASK was identified in the hypothalamic areas involved in feeding behavior, and its expression was regulated under fasting/refeeding conditions [104, 105]. It was proposed as a hypothalamic and liver nutrient sensor and a general regulator of glucose metabolism and cellular energy. Moreover, PASK−/− mice resist diet-induced obesity [93]; it might therefore be understood that PASK could control the hypothalamic function related to intake control. For example, elevated glucose levels decrease mRNA coding to PASK in VMH and LH areas in hypothalamic organotypic cultures and in neuroblastoma N2A cells [104]. The PASK expression is also regulated *in vivo* in response to fasting/refeeding conditions. This effect is clearer in LH: mRNA coding to PASK is lower under fasting conditions and increases in response to refeeding conditions [105]. The effect observed after refeeding *in vivo* is the opposite to the glucose effect found in VMH and LH in hypothalamic organotypic cultures and neuroblastoma N2A cells. However, the effect is similar to those produced in the presence of both glucose and the anorexigenic peptide GLP-1 (an incretin release from intestinal L-cells in response to feeding) [106, 107]. The role of PASK in the hypothalamus would be similar to other well-known metabolic sensors, such as AMPK and mTORC1. The activation of AMPK and mTORC1 is coordinated and antagonistic. While AMPK is activated by a fall in energy, mTORC1 is activated by its increase. Hypothalamic metabolic sensors, such as AMPK and mTORC1, therefore play an important role in feeding behavior, body weight homeostasis, and energy balance (see Section 2.1). These sensors respond to changes in nutrient levels in the VMH and LH (hypothalamic areas involved in feeding behavior) and in neuroblastoma N2A cells, and those effects are modulated by the GLP-1 in lean and

Studies in PASK−/− mice have indicated that PASK-deficiency involves a downregulation of mRNA levels coding to AMPKα2 in VMH, and slightly so in LH [105], while impairing the coordination of the AMPK and mTORC1/S6K1 pathways. Thus, both the AMPK and mTORC1/S6K1 pathways are surprisingly activated at the same time under fasting and feeding conditions in PASK−/− mice [105]. This finding could mean that the inhibition of mTORC1/S6K through AMPK activation requires the coordinated phosphorylation of TSC2 by Glycogen synthase kinase 3β (GSK3β) [59], which is a PASK substrate *in vitro,* and PASK deficiency could therefore alter hypothalamic GSK3β activity [108]. Additionally, this study has found that the exendin-4 regulatory effect on metabolic sensor activity is lost in PASK−/− mice, and the anorexigenic properties of exendin-4 significantly reduced, suggesting that PASK could be a mediator in the brain GLP-1 signaling pathway. Some of the antidiabetogenic effects of exendin-4 might be modulated through these processes. This means that hypothalamic PASK, interacting with AMPK and mTORC1 pathways, and in coordination with anorexigenic/orexigenic peptides, could be a key enzyme in food intake control, and in peripheral tissue functions, such as brown adipose tissue thermogenesis, pancreatic insulin secretion, etc. However, more studies are needed to clarify this hypothesis and the putative molecular mechanism of PASK

The downregulation of mRNA coding to AMPKα2 and the modulation of the GLP-1 effects in hypothalamus in PASK−/− mice suggest that both effects may also be regulating thermogenesis in BAT and the browning of white fat, as both processes

are mediated by the inhibition of hypothalamic AMPK [109, 110].

**352**

actions in whole-body physiology.

obese rats [57].

As well as acting in hypothalamic functions, PASK also has key functions in the peripheral tissues. For example, diabetes and PASK have been linked, as a human mutation of the *PASK* gene has been correlated with maturity-onset diabetes of the young (MODY). This mutation increases kinase activity and decreases glucosestimulated insulin secretion by the pancreas [111]. In addition, decreased PASK expression in pancreatic islets has been reported in human T2D [88]. The PASK function in peripheral tissues could be crucial for maintaining metabolic and energy homeostasis.
